Novel optically active phosphorus-chiral diphosphetanes, intermediates of the same, and transition metal complexes containing the diphosphetanes as the ligand

ABSTRACT

The present invention provides a novel optically active phosphorus-chiral diphosphetane compound useful as a ligand of a transition metal catalyst which is used for catalytic asymmetric synthesis such as asymmetric hydrogenation reaction and the like, the ligand capable of creating a stable asymmetric space when coordinating to a central metal, an intermediate of the compound, and a transition metal complex catalyst having the compound as a ligand. 
 
The optically active diphosphetane compound of the present invention has a structure represented by formula (1):  
                 
(wherein R represents a linear, branched, or cyclic alkyl group having 2 to 20 carbon atoms).

TECHNICAL FIELD

The present invention relates to a novel optically activephosphorus-chiral diphosphetane compound, an intermediate therefor, anda transition metal complex having the compound as a ligand.

BACKGROUND ART

Catalytic asymmetric synthesis reaction using an optically activecatalyst (referred to as an “asymmetric catalyst” hereinafter) iscapable of synthesizing a large amount of an optically active compoundusing a very small amount of an asymmetric catalyst, and is thus highlyvalued in industrial use. In particular, a synthesis method referred toas “asymmetric reduction” has the advantage of high reaction efficiencyand the advantage that by-products such as an inorganic salt and thelike are not produced because of use of hydrogen gas as a raw material.Therefore, this synthesis method is economical and harmonizes withenvironments.

The catalytic asymmetric synthesis reaction is aimed at producing aproduct with high optical purity, the optical purity depending on theperformance of the asymmetric catalyst used in the reaction. Although atransition metal complex is generally used as the asymmetric catalyst,the optical purity of a reaction product is mostly determined by thetype of the asymmetric space created by the ligand coordinating to atransition metal of the complex at a reaction site. Therefore, indevelopment of an asymmetric catalyst, it is most important to designthe configuration of a ligand so as to realize excellent catalyticactivity and stereoselectivity.

In recent years, asymmetric ligands have been actively studied, andvarious asymmetric ligands have been developed. In particular, phosphineligands play an important role in catalytic asymmetric synthesisreaction using a transition metal complex. A huge amount of ligands hasbeen designed and synthesized so far.

The inventors of the present invention proposed1,2-bis(alkylmethylphosphino)ethane capable of efficientlyasymmetrically hydrogenating various α,β-unsaturated β-amino acids andesters thereof, having a phosphorus-chiral trialkyl group, andrepresented by the following formula (4):

(wherein R represents cyclopentyl, cyclohexyl, tert-butyl,1,1-diethylpropyl, or 1-adamantyl) (Non-patent Document 1).

Among ligands having phosphorus-containing heterocyclic rings, ligandshaving strong structures due to heterocyclic rings are known to suppressthe number of conformations of a chelate formed by coordination to acentral metal and create a stable asymmetric space (Non-patent Document2).

However, optically active phosphorus-chiral diphosphine represented byformula (4) has no heterocyclic ring, and it is thus difficult to say,depending on the substituent represented by R and bonded to eachphosphorus atom, that the structure of the ligand is stable.

[Non-patent Document 1]

J. Am. Chem. Soc., 1998, 120, pp. 1635-1636

[Non-patent Document 2]

J. Am. Chem. Soc., 1993, 115, pp. 10125-10138

DISCLOSURE OF THE INVENTION

Accordingly, an object of the present invention is to provide a noveloptically active phosphorus-chiral diphosphetane compound useful as aligand of a transition metal catalyst which is used for catalyticasymmetric synthesis such as asymmetric hydrogenation reaction and thelike, the ligand capable of creating a stable asymmetric space whencoordinating to a central metal, an intermediate of the compound, and atransition metal complex catalyst having the compound as a ligand.

In the above-mentioned situation, the intensive research conducted bythe inventors of the present invention resulted in the achievement ofthe present invention. In other words, in a first aspect of the presentinvention, there is provided an optically active diphosphetane compoundrepresented by formula (1):

(wherein R represents a linear, branched, or cyclic alkyl group having 2to 20 carbon atoms).

In a second aspect of the present invention, there is provided adiphosphetane compound represented by formula (2):

(wherein R represents the same as the above, X represents a borontrihydride group, an oxygen atom, or a sulfur atom, and ═══ represents asingle bond when X is a boron trihydride group or a double bond when Xis an oxygen atom or sulfur atom).

In a third aspect of the present invention, there is provided aphosphetane compound used as an intermediate for producing thediphosphetane compound represented by formula (2), the phosphetanecompound being represented by formula (3):

(wherein R, X, and ═══ represent the same as the above).

In a fourth aspect of the present invention, there is provided atransition metal complex including the optically active diphosphetanecompound represented by formula (1) as a ligand.

BEST MODE FOR CARRYING OUT THE INVENTION

An optically active phosphorus-chiral diphosphetane compound of thepresent invention is a phosphorus-chiral diphosphetane compound having aconfiguration represented by formula (1):

In the optically active phosphorus-chiral diphosphetane compoundrepresented by formula (1), Rs are each a linear, branched, or cyclicalkyl group having 2 to 20 carbon atoms. Examples of such an alkyl groupinclude ethyl, isopropyl, n-propyl, isobutyl, n-butyl, sec-butyl,tert-butyl, isoheptyl, n-heptyl, isohexyl, n-hexyl, cyclopentyl,cyclohexyl, 1-methylcyclohexyl, and adamantyl. Also, Rs may be the sameor different.

In this compound, the phosphorus atom at the 1-position and the carbonatom at the 2-position in each phosphetane skeleton have respectiveasymmetric points, and the absolute configuration is designated by(1S,1′S,2R,2R′) according to a CIP method. The compound also has theproperty of being easily-oxidizable.

Examples of the compound represented by formula (1) include thefollowing:

-   (1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-ethyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-isopropyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-n-propyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-isobutyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-n-butyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-isoheptyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-n-heptyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-isohexyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-n-hexyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-cyclopentyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-cyclohexyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-di-1-methylcyclohexyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-ethyl-isopropyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-ethyl-n-propyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-ethyl-isobutyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-ethyl-n-butyl-[2,2′]-diphosphetane,-   (1S,1S′,2R,2R′)-1,1′-ethyl-sec-butyl-[2,2′]-diphosphetane, and-   (1S,1S′,2R,2R′)-1,1′-ethyl-tert-butyl-[2,2′]-diphosphetane.

A diphosphetane compound of the present invention is represented byformula (2):

In this formula, R represents the same as the above, X represents aboron trihydride group, an oxygen atom, or a sulfur atom, and ═══represents a single bond when X is a boron trihydride group or a doublebond when X is an oxygen atom or sulfur atom.

The diphosphetane compound of the present invention is an intermediatefor producing the compound represented by formula (1). According to aCIP method, the absolute configuration of the compound represented byformula (2) in which a boranato group is bonded is designated by(1S,1′S,2R,2R′), and that of the compound in which an oxygen atom orsulfur atom is bonded is designated by (1R,1R′,2R,2R′)

Unlike the easily-oxidizable compound represented by formula (1), thecompound of formula (2) can be handled in air and is easy to handle.Also, the compound can be purified by recrystallization because of itshigh crystallinity.

Examples of the compound represented by formula (2) include thefollowing:

-   (1R,1R′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-ethyl-[2,2′]-diphosphetanyl 1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-isopropyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-n-propyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-isobutyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-n-butyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-isoheptyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-n-heptyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-isohexyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-n-hexyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-cyclopentyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-cyclohexyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-1-methylcyclohexyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1,′-ethyl-isopropyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-n-propyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-isobutyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-n-butyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-sec-butyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-tert-butyl-[2,2′]-diphosphetanyl    1,1′-disulfide,-   (1R,1R′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-ethyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-isopropyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-n-propyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-isobutyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-n-butyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-isoheptyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-n-heptyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-isohexyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-n-hexyl-[2,2′]-diphosphetanyl 1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-cyclopentyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-cyclohexyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-di-1-methylcyclohexyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-isopropyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-n-propyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-isobutyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-n-butyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-sec-butyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1R,1R′,2R,2R′)-1,1′-ethyl-tert-butyl-[2,2′]-diphosphetanyl    1,1′-dioxide,-   (1S,1′S,2R,2′R)-1,1′-di-tert-butyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-ethyl-[2,2′]-diphosphetanyl 1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-isopropyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-n-propyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-isobutyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-n-butyl-[2,2′]-diphosphetanyl    1,1′-diboranato,-   (1S,1′S,2R,2′R)-1,1′-di-isoheptyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-n-heptyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-isohexyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-n-hexyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-cyclopentyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-cyclohexyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-di-1-methylcyclohexyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-ethyl-isopropyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-ethyl-n-propyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-ethyl-isobutyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-ethyl-n-butyl-[2,2′]-diphosphetanyl    1,1′-diboranate,-   (1S,1′S,2R,2′R)-1,1′-ethyl-sec-butyl-[2,2′]-diphosphetanyl    1,1′-diboranate, and-   (1S,1′S,2R,2′R)-1,1′-ethyl-tert-butyl-[2,2′]-diphosphetanyl    1,1′-diboranate.

A phosphetane compound of the present invention is a compoundrepresented by formula (3):

In this formula, R, X, and ═══ represent the same as the above.

The phosphetane compound of the present invention is an intermediate forproducing the compound represented by formula (2). In the compoundrepresented by formula (3), a boron trihydride group, an oxygen atom ora sulfur atom is bonded to a phosphorus atom, the phosphorus atom beingtetravalent or pentavalent. Therefore, a phosphine compound unstablewhen having trivalency is stabilized and is made easy to handle. Namely,a boron trihydride group, an oxygen atom or a sulfur atom is boned to aphosphorus atom to function as a so-called protective group for thephosphorus atom.

Examples of the compound represented by formula (3) include1-tert-butyl-phosphetane 1-sulfide, 1-ethyl-phosphetane 1-sulfide,1-isopropyl-phosphetane 1-sulfide, 1-n-propyl-phosphetane 1-sulfide,1-isbutyl-phosphetane 1-sulfide, 1-n-butyl-phosphetane 1-sulfide,1-isoheptyl-phosphetane 1-sulfide, 1-n-heptyl-phosphetane 1-sulfide,1-isohexyl-phosphetane 1-sulfide, 1-n-hexyl-phosphetane 1-sulfide,1-cyclopentyl-phosphetane 1-sulfide, 1-cyclohexyl-phosphetane 1-sulfide,1-1-methylcyclohexyl-phosphetane 1-sulfide, 1-adamantyl-phosphetane1-sulfide, 1-tert-butyl-phosphetane 1-oxide, 1-ethyl-phosphetane1-oxide, 1-isopropyl-phosphetane 1-oxide, 1-n-propyl-phosphetane1-oxide, 1-isobutyl phosphetane 1-oxide, 1-n-butyl-phosphetane 1-oxide,1-isoheptyl-phosphetane 1-oxide, 1-n-heptyl-phosphetane 1-oxide,1-isohexyl-phosphetane 1-oxide, 1-n-hexyl-phosphetane 1-oxide,1-cyclopentyl-phosphetane 1-oxide, 1-cyclohexyl-phosphetane 1-oxide,1-1-methylcyclohexyl-phosphetane 1-oxide, 1-adamantyl-phosphetane1-oxide, 1-boranato-1-tert-butyl phosphetane,1-boranato-1-ethyl-phosphetane, 1-boranato-1-isopropyl-phosphetane,1-boranato-1-n-propyl-phosphetane, 1-boranato-1-isobutyl-phosphetane,1-boranato-1-n-butyl-phosphetane, 1-boranato-1-sec-butyl-phosphetane,1-boranato-1-isoheptyl-phosphetane, 1-boranato-1-n-heptyl-phosphetane,1-boranato-1-isohexyl-phosphetane, 1-boranato-1-n-hexyl-phosphetane,1-boranato-1-cyclopentyl-phosphetane,1-boranato-1-cyclohexyl-phosphetane,1-boranato-1-1-methylcyclohexyl-phosphetane, and1-boranato-1-adamantyl-phosphetane.

An example of a process for producing the optically activephosphorus-chiral diphosphetane compound is represented by the followingreaction formula:

The compound of formula (3) can be produced by a first step in whichmonoalkylphosphine (A) used as a raw material is reacted with1,3-propanediol ester, 1,3-dihalogenylpropane, or 1,3-propanediol cyclicsulfate and then reacted with a borane complex, an oxidizing agent, or asulfurizing agent. The compound of formula (2) can be produced by asecond step of coupling the compound of formula (3). The compound offormula (1) can be produced by a third step of removing borane, oxygen,or sulfur from the compound of formula (2).

In the first step, monoalkylphosphine (A) is reacted with1,3-propanediol ester, 1,3-dihalogenylpropane, or 1,3-propanediol cyclicsulfate in the presence of tert-butyl lithium and then reacted with aborane complex, an oxidizing agent, or a sulfurizing agent. Themonoalkylphosphine used as a raw material is a compound in which onehydrogen of the phosphine is substituted by a linear or branched alkylgroup having 2 to 20 carbon atoms. Examples of the phosphine includetert-butylphosphine, ethylphosphine, isopropylphosphine,n-propylphosphine, isbutylphosphine, n-butylphosphine,sec-butylphosphine, isoheptylphosphine, n-heptylphosphine,isohexylphosphine, n-hexylphosphine, cyclopentylphosphine,cyclohexylphosphine, and 1-methylcyclohexylphosphine. As the phosphine,commercially available phosphine may be used. Alternatively, phosphinesynthesized by addition reaction of phosphine gas and an olefin orreduction of alkyldihalogenylphosphine, which is prepared fromphosphorus halide and an alkyl Grignard reagent, with lithium aluminumhydride or the like may be used. The monoalkylphosphine used preferablyhas a purity of 95% or more from the viewpoint of suppressingby-products.

As the other raw material, 1,3-propanediol ester or1,3-dihalogenylpropane, a commercial product may be used. Examples of1,3-propanediol ester include 1,3-bis(tosyloxy)propane,1,3-bis(mesyloxy)propane, and 1,3-bis(trifluoroxy)propane. Examples of1,3-dihalogenylpropane include 1,3-dibromopropane, 1,3-dichloropropane,and the like. Also, 1,3-propanediol cyclic sulfate may be synthesizedaccording to a known method, e.g., the method described in J. Am. Chem.Soc., 1993, 115, p. 10134. Among these compounds, 1,3-dichloropropane ismost preferred because of easy availability, low cost, and relativelyhigh product yield.

As n-butyl lithium, a commercially available product may be used. Fromthe viewpoint that an appropriate amount can be added, and side reactioncan be prevented, preferably, the concentration of n-butyl lithium isprecisely determined by titration in advance.

When X in the compound represented by formula (3) and produced by thefirst step is a borane complex, a borane-THF complex, a borane-dimethylsulfide complex, a borane-methyl sulfide complex, or the like can beused. When X is an oxygen atom, an oxidizing agent such as hydrogenperoxide or the like can be used. When X is a sulfur atom, a sulfurizingagent such as sulfur powder or the like can be used.

In the first step, first, monoalkylphosphine (A) is reacted with1,3-propanediol ester, 1,3-dihalogenylpropane, or 1,3-propanediol cyclicsulfate in the presence of tert-butyl lithium.

The solvent used is not particularly limited as long as it does notreact with a reaction agent and the like. However, diethyl ether,tetrahydrofuran (referred to as “THF” hereinafter), n-hexane, toluene,and the like can be used alone or as a mixture of two or more. Thesolvent is preferably dehydrated by an ordinary method before use.

The reaction conditions and temperature depend on the electrophilicreagent used. For example, when 1,3-dichloropropane is used, it isnecessary that a solution of alkylphosphine and 1,3-dichloropropane iscooled to −78 to −50° C. and preferably −70 to −78° C., and n-butyllithium is slowly added dropwise. The inside of the reactor used ispreferably sufficiently dried and replaced with inert gas from theviewpoint of prevention of moisture deactivation of n-butyl lithium andoxygen oxidation of the phosphine. Then, the reaction solution is heatedto −20 to 0° C., and any one of a borane complex, an oxidizing agent,and a sulfurizing agent is added to the reaction solution. Afterreaction for 0.5 to 2 hours, pure water is added to the reactionsolution to terminate the reaction. An aqueous layer is separated fromthe resultant mixture of an organic layer and the aqueous layer, and theorganic layer is washed with pure water and then an aqueous inorganicsalt solution, and dehydrated. After, the organic solvent is removed,the residue is dried to obtain a crude phosphetane compound. Theresulting crude phosphetane compound can be purified by an ordinarymethod such as recrystallization, column chromatography, distillation,or the like.

In the second step, the compound represented by formula (3) is coupled.

First, (−)-sparteine and a solvent are added to a reactor and cooled to−50° C. or less, and an n-butyl lithium or sec-butyl lithium solution isadded to the reactor. The resultant mixture is stirred to prepare abutyl lithium/(−)-sparteine complex.

As the (−)-sparteine, a commercially available reagent is preferablydistilled and then used.

As the n-butyl lithium or sec-butyl lithium, a commercially availablecompound can be used. From the viewpoint that an appropriate amount canbe added, and side reaction can be prevented, the concentration of then-butyl lithium or sec-butyl lithium is preferably precisely determinedby titration in advance.

The reaction temperature is −50° C. or less and preferably −70° C. orless. The butyl lithium/(−)-sparteine complex is a reagent effective instereoselective deprotonation reaction of a prochiral methyl group.

Next, a solution of the purified phosphetane compound in an organicsolvent is added to a solution of the butyl lithium/(−)-sparteinecomplex, followed by reaction at −50 to −78° C. for 3 to 8 hours. Then,copper chloride is added to the reaction solution, and the reactionsolution is gradually heated to room temperature under stirring over 2to 3 hours, followed by further reaction at room temperature for 3 to 15hours. The copper chloride used is preferably sufficiently ground by amortar and dried in advance. The solvent used is not particularlylimited as long as it is an aprotic organic solvent which does notinhibit coordination of (−)-sparteine to lithium and which does notsolidify at low temperatures. As the solvent, a single solvent or amixture of two or more solvents may be used, but diethyl ether ispreferred from the viewpoint of the high formation rate of the butyllithium/(−)-sparteine complex.

The inside of the reactor is preferably sufficiently dried and replacedby inert gas before the reaction, and the reaction is preferablyperformed under an inert gas stream from the viewpoint that deactivationof the butyl lithium/(−)-sparteine complex can be prevented.

Thereafter, conc. ammonia water is added to the reaction solution toterminate the reaction. An organic layer is separated, and an aqueouslayer is subjected to extraction with a polar solvent such as aceticacid. The organic layers are collected, washed, and dehydrated, and thenthe extraction solvent is removed to obtain a crude mixture of acompound represented by formula (2). Then, the mixture is purified byordinary means such as silica gel column chromatography or the like andrecrystallization to obtain an optically pure compound represented byformula (2). The optical purity of the compound represented by formula(2) can be measured by HPLC analysis using a commercial optically activecolumn.

In the third step, borane, oxygen, or sulfur is removed from thecompound represented by formula (2).

In the present invention, “borane removal” means removal of a boranatogroup bonded to a lone electron pair of each phosphorus atom of thecompound represented by formula (2). A method for removing a boranatogroup is not particularly limited, and any general method for removingborane may be used. For example, a method of heating in an aminesolvent, a method of reacting with a superstrong acid such astrifluoromethanesulfonic acid or the like and then neutralizing with analkali, or the like may be used. In the method of heating in an aminesolvent, the reaction temperature is 50 to 80° C. and preferably 60 to70° C. With the temperature lower than 50° C., the reaction rate is low,while with the temperature over 80° C., optical purity decreases. Thereaction time is preferably 1 to 3 hours.

In the present invention, “deoxidation” means removal of an oxygen atombonded to a lone electron pair of each phosphorus atom of the compoundrepresented by formula (2), and is reduction reaction. The reductionreaction is not particularly limited, and any general reduction reactioncan be used. For example, trichlorosilane, phenylsilane, or the like canbe used.

In the present invention, “desulfurization” means removal of a sulfuratom bonded to a lone electron pair of each phosphorus atom of thecompound represented by formula (2), and is reduction reaction. Thereduction reaction is not particularly limited, and any generalreduction reaction can be used. For example, a reduction method usinghexachlorodisilane, a reduction method using Raney nickel, or the likecan be used. In the reduction method using hexachlorodisilane, thereaction temperature is 20 to 90° C. and preferably 80 to 90° C., andthe reaction time is 1 to 6 hours.

As described above, borane removal, deoxidization, or desulfurization ofthe compound represented by formula (2) can produce a compoundrepresented by formula (1) while maintaining the configuration at eachphosphorus atom. Therefore, the compound of formula (2) is a compoundsuitable for producing the compound of formula (1).

The configurations of the compound of formulae (1) and the compound offormula (2) can be confirmed by single-crystal X-ray structuralanalysis.

The compound represented by formula (1) can be reacted with a transitionmetal complex represented by formula (5):[M(A)p(B)q]n  (5)to produce a transition metal complex having the compound of formula (1)as a ligand in the reaction system. The resulting transition metalcomplex can be used in catalytic asymmetric synthesis reaction.

In formula (5), M is a transition metal serving as a central metal ofthe transition metal complex and is preferably rhodium, ruthenium,palladium, or copper.

In formula (5), A is a ligand of the transition metal complex and is anelectron-donating ligand which is exchanged with the compound of formula(1) serving as a ligand in the reaction system. From the viewpoint ofeasy ligand exchange and easy production of an asymmetric metal complexhaving the compound of formula (1) as a ligand in the reaction system,ethylene, a hydrocarbon diene, a carbonyl group, allyl anion, or2-methylallyl anion is particularly preferred. Examples of thehydrocarbon diene include cycloocta-1,5-diene (also referred to as “cod”hereinafter), norbornadiene (also referred to as “nbd” hereinafter), andthe like.

In formula (5), B is a ligand of the transition metal complex and is aligand which is not exchanged with the compound of formula (1) servingas a ligand. Examples of B include a fluorine atom, a bromine atom, aniodine atom, an acetoxyl group (also referred to as “OAc” hereinafter),a trifluorosulfonyl group (also referred to as “OTf” hereinafter), anitrile group, and dimethylformamide.

In formula (5), p represents an integer of 0 to 2, q represents aninteger of 0 to 2, (p+q) is 1 or more, and n represents an integer of 1or 2. However, these numbers vary depending on the type and valency ofthe central metal M. When p is 1 or 2, for example, Rh[(cod)Cl]₂produces a transition metal complex by ligand exchange of the compoundof formula (1) with cod. When p is 0, for example, Cu(OTf)₂ produces atransition metal complex by direct coordination of the compound offormula (1) to copper without ligand exchange.

When the compound of formula (1) is added to a reaction system in whichthe transition metal complex of formula (5) is present, a transitionmetal complex is produced by ligand exchange or direct coordination inthe reaction system. The resultant transition metal complex can be usedin catalytic asymmetric synthesis reaction because the compound offormula (1) serving as a ligand creates an effective asymmetric space.

An example of the asymmetric synthesis reaction using the transitionmetal complex produced in the reaction system is asymmetric reductionreaction.

When the compound of formula (1) and the transition metal complex offormula (5) are present in the same reaction system, a transition metalcomplex is rapidly produced. Therefore, asymmetric reduction reactioncan be performed by a method in which the compound of formula (1) andthe transition metal complex of formula (5) are successively added to,for example, an asymmetric reduction reactor to produce an asymmetrictransition metal complex in the reaction system containing a rawmaterial. Alternatively, the compound of formula (1) and the transitionmetal complex of formula (5) may be mixed to produce a transition metalcomplex, and then the resulting transition metal complex may be added toan asymmetric reduction reaction system containing a raw material.

The reaction temperature depends on the types of the reaction and rawmaterials used or the central metal of the transition metal complexused, but the temperature is about −20 to 30° C. With the temperaturelower than −20° C., the reaction rate is low, while with the temperatureover 30° C., optical purity tends to decrease. The reaction time dependson the types of the reaction and raw materials used or the central metalof the transition metal complex used, but the time is about 1 to 3hours.

Examples of the solvent used in the reaction include, but are notlimited to, saturated hydrocarbons such as hexane; aromatic hydrocarbonssuch as toluene; alcohols such as methanol; ethers such as diethyl etherand THF; halogenated hydrocarbons such as methylene chloride; andnitrites such as acetonitrile. The solvent is preferably dehydrated byan ordinary method before use from the viewpoint of prevention ofdeactivation of the transition metal complex.

The transition metal complex of the present invention is produced byreaction between the compound of formula (1) and the transition metalcomplex of formula (5) to have a structure represented by formula (6) or(7):[M(A)p(B)q(L)]  (6)[Mx(A)r(B)s(L)]⁺Y⁻  (7)

In formula (6), L represents the compound represented by formula (1),which coordinates to the central metal to create an asymmetric space.Furthermore, M, A, B, p, and q represent the same as those of thetransition metal complex of formula (5), and the values of p and q varyaccording to the type and valency of the central metal M.

In formula (7), L represents the compound represented by formula (1),and Y represents a counter anion when the transition metal complex haspositive charge. Examples of Y include a tetrafluoroboric acid group(BF₄ ⁻), a hexafluorophosphoric cid group (PF₆ ⁻), and an antimonyhexafluoride group (SbF₆ ⁻). Furthermore, M, A, and B represent the sameas those of the transition metal complex of formula (5), x represents aninteger of 1 or 2, r represents an integer of 0 to 2, s represents aninteger of 0 to 4, and r+s is 1 or more. The values of x, r, and s varydepending on the type and valency of the central metal M.

Examples of a rhodium complex include [RhCl(L)]₂, [RhBr(L)]₂, [RhI(L)]₂,[Rh(OAc) (L)]₂, and the like. Examples of a ruthenium complex include[RuCl₂(L)]₂, [RuBr₂(L)]₂, [RuCl₂(L) (DMF)]₂, [Ru₂Cl₄(L)₂]NEt₃, and thelike. Examples of a palladium complex include [PdCl(L)]₂, [PdCl₂(L)],[Pd(C₂H₄)L], and the like. Examples of a copper complex include[Cu(OTf)₂(L)], [CuCN(L)], [CuI(L)], and the like.

The transition metal complex of formula (6) or (7) can be produced by aknown method, e.g., the method described in “Jikken Kagaku Kouza (4thedition) (Experimental Chemistry) 18, Organometallic Complex”, edited byThe Chemical Society of Japan, Maruzen, 1991. Examples of a method forproducing a rhodium complex include the methods described in “JikkenKagaku Kouza (4th edition) (Experimental Chemistry) 18, OrganometallicComplex”, edited by The Chemical Society of Japan, Maruzen, 1991, pp.327-139, and J. Am. Chem. Soc., 1994, 116, pp. 4062-4066. Examples of amethod for producing a ruthenium complex include the method described in“Gosei-Kagakusha No Tameno Jikken Yuki-Kinzoku-Kagaku (ExperimentalOrganic Chemistry for Synthetic Chemists)” edited by KodanshaScientific, pp. 391-411, Maruzen, 1991. Examples of a method forproducing a copper complex include the method described in “JikkenKagaku Kouza (4th edition) (Experimental Chemistry) 18, OrganometallicComplex”, edited by The Chemical Society of Japan, Maruzen, 1991, pp.440-450.

For example, a THF solution of the compound of formula (1) is added to aTHF solution of bis(cycloocta-1,5-diene)rhodium (I) tetrafluoroborate toproduce [Rh(cycloocta-1,5-diene) (L)]⁺BF₄ ⁻ by ligand exchange. Theresultant rhodium complex having the compound of formula (1) as a ligandcan be confirmed by the chemical shift and coupling constant obtainedfrom ³¹P-NMR analysis.

The transition metal complex of formula (6) or (7) contains the compoundof formula (1) serving as a ligand which creates an effective asymmetricspace, and is thus suitable for catalytic asymmetric synthesis reaction.Therefore, the transition metal complex of formula (6) or (7) cansatisfactorily produce catalytic asymmetric reduction reaction. Thereaction raw materials, reducing agent, and nucleophilic agent used, andthe solvent, reaction temperature, and reaction time used are the sameas those for producing the transition metal complex in theabove-descried reaction system.

EXAMPLES

The present invention will be described in detail below with referenceto examples, but these examples are just examples, and the presentinvention is not limited to the examples.

Example 1 Synthesis of 1-tert-butyl-phosphetane 1-sulfide

The inside of a well-dried 2-L flask was sufficiently replaced withargon, and 150.2 g (200 mmol) of a 12% n-hexane solution of tert-butylphosphine and 18.9 mL (200 mmol) of 1,3-dichloropropane were charged inthe flask. Then, 1 L of a THF solvent was added to the flask, followedby cooling to −78° C. To the flask, 277 mL (440 mmol) of n-butyl lithiumat a concentration of 1.59 mol/L was added dropwise over 1 hour using adropping funnel. After the reaction solution was stirred at −78° C. for1 hour, the solution was heated to 0° C., and 9.6 g (300 mmol) of sulfurpowder was added to the solution at a time. After stirring at roomtemperature for 2 hours, 200 mL of pure water was carefully added toterminate reaction. An aqueous layer was separated, and an organic layerwas washed with 200 mL of pure water and 200 mL of saturated brine anddehydrated over anhydrous sodium sulfate. Then, the solvent wasdistilled off, and the resulting crude product was purified by analumina column and recrystallized from hexane to obtain 15.6 g of target1-tert-butyl-phosphetane 1-sulfide. The yield was 48%.

Physical property data

Melting point: 120.0-120.8° C.

¹H NMR (CDCl₃) δ1.30 (d, ³J_(HP)=16.4 Hz, 9H), 1.95-2.15 (m, 2H),2.25-2.65 (m, 1H), 2.45-2.65 (m, 2H), 2.60-2.80 (m, 2H),

¹³C NMR δ14.15 (d, ²J_(CP)=21.1 Hz), 23.86 (d, ²J_(CP)=2.7 Hz), 30.97(d, J_(CP)=45.35 Hz), 33.92 (d, J_(CP)=34.71 Hz)

31P NMR (¹H decoupled, CDCl₃) δ682.07 (s)

IR (KBr) 2960, 1462, 1362, 945, 718, 678 cm⁻¹

HRMS calculated value (C₇H₁₅PS (M⁺)) 162.0632, observed value 162.0631

Example 2 Synthesis of 1-boranato-1-tert-butyl-phosphetane

The inside of a well-dried 3-L flask was sufficiently replaced withargon, and 172 g (200 mmol) of a 10.6% n-hexane solution of tert-butylphosphine and 18.9 mL (200 mmol) of 1,3-dichloropropane were charged inthe flask. Then, 1.5 L of a THF solvent was added to the flask, followedby cooling to −78° C. To the flask, 171 mL (420 mmol) of n-butyl lithiumat a concentration of 2.45 mol/L was added dropwise using a droppingfunnel over 2 hours. The reaction solution was heated to 0° C. over 3hours under stirring, and 195 mL (220 mmol) of a borane-tetrahydrofurancomplex tetrahydrofuran solution at a concentration of 1.13 mol/L wasadded. After stirring at 0° C. for 1 hour, 200 mL of pure water wascarefully added to terminate reaction. An aqueous layer was separated,and an organic layer was washed with 200 mL of pure water, 100 mL of a 1mol/L aqueous hydrochloric acid solution, and 200 mL of saturated brine,and dehydrated over anhydrous sodium sulfate. Then, the resulting crudeproduct was distilled under reduced pressure to obtain 16.7 g of1-boranato-1-tert-butyl-phosphetane. The yield was 58%.

Physical property data

Melting point: 91-93° C./6 mmHg

¹HNMR (CDCl₃) δ0.67 (br q, J_(HB)=95.3 Hz, 3H), 1.22 (d, ³J_(HP)=14.0Hz, 9H), 1.95-2.10 (m, 2H), 2.15-2.30 (m, 2H), 2.30-2.45 (m, 1H),2.45-2.65 (m, 1H),

¹³C NMR δ18.00 (d, J_(CP)=38.5 Hz), 18.14 (d, ²J_(CP)=17.4 Hz), 24.5 (d,²J_(CP)=3.8 Hz), 28.4 (d, J_(CP)=19.24 Hz)

³¹P NMR (1H decoupled, CDCl₃) δ65.8 (q, J_(PB)=51.3 Hz) GCMS 143 (M-H)⁺

Example 3 Synthesis of(1R,1R′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetanyl 1,1′-disulfide

The inside of a well-dried 300-mL two-necked flask was sufficientlyreplaced with argon, and 8.44 g (36 mmol) of sparteine and then 70 mL ofdry ether were added using a syringe, followed by stirring. Aftercooling to −78° C. in a dry ice/methanol bath, s-BuLi (36 mmol) wasadded to the resultant mixture using a syringe, followed by stirring for1 hour. To the flask, a solution of 4.87 g (30 mmol) of1-tert-butyl-phosphetane 1-sulfide prepared in Example 1 in 30 mL ofdehydrated toluene was added using a dropping funnel at a reactiontemperature kept at −78° C. The dropping time was 1 hour. After thedropping was completed, the reaction solution was stirred at −78° C. for5 hours, and then 6.05 g (45 mmol) of copper chloride was added at atime. After the flask was returned to room temperature over 2 hours, thesolution was further stirred at room temperature for 12 hours. After thestirring, 150 mL of 25% ammonia water was added to terminate reaction.Furthermore, 100 mL of ethyl acetate was added for a separationoperation. An aqueous layer was subjected to three times of extractionwith 100 mL of ethyl acetate each, and the collected organic layers werewashed with 5% ammonia, 2M HCl, pure water, and brine, dehydrated overanhydrous sodium sulfate, and then concentrated.

The concentrate was roughly purified by a short column (silica gel,ethyl acetate) and then purified by flash chromatography (silica gel,hexane/ethyl acetate=5:1) to obtain a mixture of an optically activecompound and a meso compound in a yield of about 40%. The mixture waspurified by flash chromatography (silica gel, hexane/acetone=5:1) toobtain the optically active compound with an optical purity of 95% ee ina yield of about 30%. The resulting compound was recrystallized fromethyl acetate four times to finally obtain 490 mg of diphosphetane withan optical purity of 99% ee or more. The yield was 10%.

Physical property data

¹H NMR (CDCl₃) δ1.30 (d, ³J_(HP)=17.0 Hz, 18H), 1.95-2.15 (m, 4H),2.25-2.50 (m, 2H), 2.55-2.75 (m, 2H), 3.60-3.84 (m, 2H), ¹³C NMR δ19.53(dd, 21.7 Hz, 18.0 Hz), 24.3 (s), 25.85 (dd, J_(CP)=47.2 Hz, 1.8 Hz),35.41 (dd, J_(CP)=34.2 Hz, 2.5 Hz), 38.02 (dd, J_(CP)=44.7 Hz,²J_(CP)=6.8 Hz)

³¹P NMR (1H decoupled, CDCl₃) δ90.29 (s)

IR (KBr) 2970, 2947, 2364, 1460, 1366, 896, 808, 708, 646 cm⁻¹

HRMS calculated value (C₁₄H₂₉P₂S₂ (M+H⁺)) 323.1186, observed value323.1198

Elemental analysis calculated value (C₁₄H₂₈P₂S₂): C, 52.15; H, 8.75,observed value: C, 52.24; H, 8.80.

[α]²⁵ _(D)−160⁰ (95% ee, c 0.99, CHCl₃)

Example 4 Synthesis of(1S,1S′,2R,2R′)-1,1′-diboranato-1,1′-di-tert-butyl-[2,2′]-diphosphetane

The inside of a well-dried 300-mL two-necked flask was sufficientlyreplaced with argon, and 4.32 g (30 mmol) of1-boranato-1-tert-butyl-phosphetane prepared in Example 2 was charged inthe flask. To the flask, 8.44 g (36 mmol) of sparteine and then 70 mL ofdry ether were added using a syringe, followed by stirring. Aftercooling to −78° C. in a dry ice/methanol bath, s-BuLi (36 mmol) wasslowly added to the resultant mixture using a syringe. After theaddition, the mixture was stirred at −78° C. for 3 hours, and 6.05 g (45mmol) of copper chloride was added at a time. After the flask wasreturned to room temperature over 2 hours, the solution was furtherstirred at room temperature for 12 hours. After the stirring, 150 mL of25% ammonia water was added to terminate reaction. Furthermore, 100 mLof ethyl acetate was added for a separation operation. An aqueous layerwas subjected to three times of extraction with 100 mL of ethyl acetateeach, and the collected organic layers were washed with 5% ammonia, 2MHCl, pure water, and brine, dehydrated over anhydrous sodium sulfate,and then concentrated. The concentrate was purified by flashchromatography (silica gel, hexane/ethyl acetate=20:1), and the obtainedsolute was recrystallized from hexane to obtain 650 mg of target(1S,1S′,2R,2R′)-1,1′-diboranato-1,1′-di-tert-butyl-[2,2′]-diphosphetane.The yield was 15%. As a result of measurement of the optical purity ofthe target compound by chiral HPLC (Daicel OD-H, hexane:2-propanol=99:1,0.5 mL/min, UV 210 nm), the optical purity was 100% ee.

Physical property data

Melting point: 147-149° C. (decomposition)

¹H NMR (CDCl₃) δ0.60 (br q, J_(HB)=106.0 Hz, 6H), 1.23 (d, 18H),1.64-1.81 (m, 2H), 1.96-2.20 (m, 4H), 2.30-2.62 (m, 2H), 3.10-3.34 (m,2H),

¹³C NMR δ13.74 (d, J_(CP)=39.8 Hz), 22.84 (dd, ²J_(CP)=13.1 Hz,²J_(CP)=15.5 Hz), 24.89 (d, ³J_(CP)=3.1 Hz), 29.64 (d, J_(CP)=16.8 Hz),32.15 (d, J_(CP)=34.2 Hz)

³¹P NMR (1H decoupled, CDCl₃) δ667.8-69.9 (m)

Example 5 Synthesis of(1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane

In a 100-mL two-necked flask, 129 mg (0.4 mmol) of(1R,1R′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetanyl 1,1′-disulfidewas dissolved in 8 mL of degassed dry benzene under an argon stream. Tothe flask, 1.56 g (5.8 mmol) of hexachlorodisilane was added. Thereaction solution was refluxed under heating for 3 hours and then cooledto 0° C. To the cooled flask, a 30% aqueous solution of sodium hydroxidewas carefully added dropwise using a dropping funnel. After the droppingwas completed, the mixture in the flask was heated to 50° C. understirring until an aqueous layer became transparent. An organic layer wasremoved using a syringe, and the aqueous layer was subjected to twotimes of extraction with degassed hexane. The organic layers werecollected and dehydrated over anhydrous. sodium sulfate, and the solventwas distilled off to obtain a crude product. The thus-obtained crudeproduct was purified by a basic alumina column to obtain 78 mg of(1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane. The yield was75%. The resultant compound was easily-oxidizable and thus led directlyto a rhodium complex.

Example 6 Synthesis of [rhodium (I)((1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane)(norbornadiene)]tetrafluoroborate

In an argon stream, 78 mg (0.3 mmol) of(1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane prepared inExample 5 was dissolved in 4 mL of THF. The resultant solution was addedto a suspension cooled to 0′ C. and containing 102 mg (0.27 mmol) of[rhodium (I) (dinorbornadiene)]tetrafluoroborate and 10 mL of THF. Thereaction solution was stirred at room temperature for 3 hours. After thecompletion of reaction, an insoluble substance was filtered off using acerite column under an argon stream. The filtrate was concentrated withan evaporator, and the purified orange solid was washed twice with 5 mLof diethyl ether and dried under reduced pressure. The resultant crudeproduct was recrystallized from a small amount of THF to obtain 31 mg ofthe target rhodium catalyst. The yield was 20%.

Physical property data

³¹P NMR (1H decoupled, CDCl₃) δ114.90 (d, J_(PRh)=147 Hz)

Example 7 Synthesis of(1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane

In a 50-mL two-necked flask, 143 mg (0.5 mmol) of(1S,1S′,2R,2R′)-1,1′-diboranato-1,1′-di-tert-butyl-[2,2′]-diphosphetanewas dissolved in 3 mL of degassed dry dichloromethane under an argonstream, and the resultant solution was cooled to 0° C. To the flask,0.68 mL (5 mmol) of a tetrafluoroboric acid-diethyl ether complex wasadded using a microsyringe. The reaction solution was stirred at roomtemperature for 12 hours and then cooled to 0° C. To the cooled flask,12 mL of a 1 mol/L aqueous solution of sodium hydrogen carbonatesolution was carefully added dropwise using a dropping funnel. After thedropping was completed, the resultant mixture was stirred for 2 hours,and degassed diethyl ether was added to extract an organic substancethree times. The extracted organic layers were collected and dehydratedover anhydrous sodium sulfate, and the solvent was distilled off toobtain a crude product. The thus-obtained crude product was purified bya basic alumina column to obtain 107 mg of(1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane. The yield was83%. The resultant compound was easily-oxidizable and thus led directlyto a rhodium complex.

Example 8 Synthesis of [rhodium (I)((1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane)(norbornadiene)]hexafluorophosphate

In an argon stream, 107 mg (0.41 mmol) of(1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane prepared inExample 7 was dissolved in 2 mL of dichloromethane. The resultantsolution was added to a suspension cooled to 0° C. and containing 160 mg(0.37 mmol) of [rhodium (I)(dinorbornadiene)]hexafluorophosphate and 5mL of THF. The reaction solution was stirred at room temperature for 3hours. After the completion of reaction, an insoluble substance wasfiltered off using a membrane filter under an argon stream. The filtratewas concentrated with an evaporator, and the produced orange solid waswashed twice with 5 mL of diethyl ether and dried under reduced pressureto obtain the title compound.

Physical property data

Melting point: 130° C. (decomposition)

¹H NMR (CDCl₃) δ 1.23 (d, J_(HB)=12.2 Hz, 18H), 1.83 (m, 2H), 1.07 (m,2H), 2.21 (m, 4H), 2.43 (m, 2H), 2.77 (m, 2H), 4.26 (s, 2H), 5.74 (d,J=25.1 Hz, 2H), 5.75 (d, J=4.6 Hz, 2H),

³¹P NMR (1H decoupled, CDCl₃) δ 114.8 (d, J_(P-Rh)=148 Hz), 143.7 (h,J_(P-F)=711 Hz)

IR (KBr) 2940, 1465, 1310, 1180, 840, 560 cm⁻¹

Example 9 Asymmetric Reduction of Methyl α-acetamidocinnamate UsingRhodium Catalyst

In a 50-mL glass autoclave containing a magnetic stirrer, 219 mg (1mmol) of methyl α-acetamidocinnamate used as a substrate and 1 mg (0.002mmol) of [rhodium (I)((1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane)(norbornadiene)]tetrafluoroboratesynthesized in Example 6 and used as a catalyst were charged. The insideof the reaction system was sufficiently replaced with hydrogen gas, andthen a cock of the autoclave was partially opened to rapidly add 5 mL ofmethanol as a solvent and then closed. The autoclave was cooled byimmersion in a dry ice/ethanol bath, and the reaction system wasevacuated, followed by vacuum breaking with hydrogen gas (2 atm). Thisoperation was repeated four times, and then the bath was removed. Thereaction system was stirred at room temperature for 3 hours until thehydrogen pressure was no more decreased. After the completion ofreaction, vacuum breaking was carefully performed with hydrogen gas, andthe resultant reaction solution was analyzed directly with chiral HPLC(Daicel OD-H, hexane: 2-propanol=9:1). As a result of the analysis, areductant with an optical purity of 96.8% ee was obtained in a reactionyield of 99% or more.

Asymmetric Hydrogenation Reaction of Dehydroamino Acid Derivative andEnamide Derivative Examples 10 to 22

In a 50-mL autoclave, 6 mg (1.0×10⁻² mmol) of the [rhodium (I)((1S,1S′,2R,2R′)-1,1′-do-tert-butyl-[2,2′]-diphosphetane)(norbornadiene)]hexafluorophosphatesynthesized in Example 8 and used as a catalyst and 1 mmol of thedehydroamino acid derivative (or enamide derivative) shown in Table 1were charged. Then, the system was evacuated and purged with hydrogenfour times. The autoclave was returned to normal pressure, and a cockwas opened to rapidly add 4 mL of degassed dehydrated methanol from thecock using a syringe and then closed. The reactor was cooled with dryice/ethanol, and then the reaction system was again evacuated and purgedwith hydrogen four times. After the hydrogen pressure was set to apredetermined value, the refrigerant was removed, and the reactionsystem was stirred with a magnetic stirrer until hydrogen consumptionwas stopped. After the completion of reaction, the reaction solution waspassed through silica gel column chromatography (developing solvent:ethyl acetate) to remove the catalyst, and then the residue wasconcentrated with an evaporator to obtain a reduced product. In anyreaction, the yield was about 100%. The optical purity (ee) of eachproduct was analyzed with chiral HPLC or chiral GC. The results areshown in Table 1. These results were obtained at a ratio ofsubstrate:catalyst=100:1. TABLE 1 Asymmetric hydrogenation reaction ofdehydroamino acid derivative and enamide derivative using [rhodium (I)((1S,1S′,2R,2R′)-1,1′-do-tert-butyl-[2,2′]- diphosphetane)(norbornadiene)] hexafluorophosphate (cat.) as a catalyst

Hydrogen Reaction Example R¹ R² R³ pressure (atm) time (h) ee (%)(Conf.)^(b,c) 10 Ph H CO₂Me 1 1 >99(R) 11 Ar^(a) H CO₂Me 1 1 >99(R) 12 HH CO₂Me 1 1 >99(R) 13 Me Me CO₂Me 6 5   15(R) 14 —(CH₂)₄— CO₂Me 6 5   1(R) 15 H H Ph 1 1 >99(R) 16 H H 4-MeOC₆H₄ 1 1   99(R) 17 H H4-O₂NC₆H₄ 1 11 >99(R) 18 Me H Ph 1 1 >99(R) 19 H Me Ph 2 1   37(R) 20 MeMe Ph 3 12   70(R) 21 H H t-C₄H₉ 1 1   93(S) 22 H H 1-adamantyl 1 1  62(S)In the table,^(a)Ar represents 3-methoxy-4-acetyloxyphenyl group^(b)Conf. represents the absolute configuration at an asymmetric pointof a product.^(c)Determined by chiral GC or chiral HPLC.

Example 23 Catalytic activity test of [rhodium (I)((1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane)(norbornadiene)]hexafluorophosphateusing asymmetric hydrogenation reaction of methylα-acetamidocinnamate:substrate:catalyst=50,000:1

In a 10-mL two-necked egg-shaped flask containing a magnetic stirrer, 2mg (3.3 μmol) of the [rhodium (I)((1S,1S′,2R,2R′)-1,1′-di-tert-butyl-[2,2′]-diphosphetane)(norbornadiene)]hexafluorophosphateprepared in Example 8 was precisely weighed and charged. The inside ofthe flask was replaced with argon, and then 2 mL of degassed anddehydrated methanol was precisely measured with a syringe and added tothe flask. The resultant mixture was stirred until the solution becamecompletely homogenous. Next, a magnetic stirrer and 779 mg (3.3 mmol) ofmethyl α-acetamidocinnamate used as a substrate were placed in a 50-mLautoclave. Then, 40 μL of a methanol solution (concentration 1.66μmol/mL) of the catalyst prepared as described above was preciselymeasured with a microsyringe and added to the autoclave. The autoclavecontained 3.3 mmol of the substrate and 6.7×10⁻² μmol of the catalyst,and thus the ratio of substrate:catalyst was 50000:1. Next, the insideof the autoclave was replaced with argon, and 4 mL of degassed anddehydrated methanol was rapidly added to the autoclave. Then, theautoclave was sealed and cooled by immersion in a dry ice/ethanol bath,and the reaction system was evacuated, followed by vacuum breaking withhydrogen gas. This operation was repeated four times, and then theinternal pressure of the autoclave was increased to 6 atm. The bath wasremoved, and the reaction system was stirred at room temperature untilthe hydrogen pressure was no more decreased. As a result, reduction ofthe gage pressure was stopped after stirring for 43 hours, and thus thetermination of the reaction was confirmed. After the reaction wasterminated, vacuum breaking was carefully performed with hydrogen gas,and the reaction solution was passed through silica gel columnchromatography (developing solvent:ethyl acetate) to remove the catalystand then concentrated with an evaporator to obtain a reduced product.The yield was about 100%. The optical purity (ee) of the product wasanalyzed with chiral HPLC (Daicel OD-H, hexane:2-propanol=9:1). As aresult of the analysis, the optical purity of the reductant was 99% ormore.

INDUSTRIAL APPLICABILITY

According to the present invention, an optically active diphosphetanecompound can be obtained, and a transition metal complex containing thecompound as a ligand is useful as an asymmetric hydrogenation catalyst.

1. An optically active diphosphetane compound represented by formula(1):

(wherein R represents a linear, branched, or cyclic alkyl group having 2to 20 carbon atoms).
 2. A diphosphetane compound represented by formula(2):

(wherein R represents the same as the above, X represents a borontrihydride group, an oxygen atom, or a sulfur atom, and ═══ represents asingle bond when X is a boron trihydride group or a double bond when Xis an oxygen atom or sulfur atom).
 3. A phosphetane compound used as anintermediate for producing the compound according to claim 2, thephosphetane compound being represented by formula (3):

(wherein R, X, and ═══ represent the same as the above).
 4. A transitionmetal complex comprising the optically active diphosphetane compoundaccording to claim 1 as a ligand.